7-150945175-G-A

Position:

• chr7-150945175-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000238.4(KCNH2):​c.*190C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 659,358 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: KCNH2 NM_000238.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.02

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 7-150945175-G-A is Benign according to our data. Variant chr7-150945175-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 910580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00352 (536/152330) while in subpopulation AFR AF= 0.0113 (471/41572). AF 95% confidence interval is 0.0105. There are 0 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 536 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.*190C>T		3_prime_UTR_variant	15/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.*190C>T		3_prime_UTR_variant	15/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.*190C>T		3_prime_UTR_variant	11/11	1
KCNH2	ENST00000684241.1	n.4503C>T		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 534 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.000473 AC: 240 AN: 507028 Hom.: 1 Cov.: 6 AF XY: 0.000443 AC XY: 116 AN XY: 262124

Gnomad4 AFR exome AF: 0.00980

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.000216

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000341

Gnomad4 NFE exome AF: 0.0000981

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00337 AC XY: 251 AN XY: 74486

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00444

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	KCNH2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2019	- -

Long QT syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41313143; hg19: chr7-150642263;